Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases

Abstract

Provided herein are hydroxypyridone derivatives, for example, a compound of Formula I, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a proliferative disease.

What is claimed is: 
     
       1. A method for treating one or more symptoms of cancer in a subject, comprising administering to the subject a compound of Formula VI: 
       
         
           
           
               
               
           
         
       
       or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; or a pharmaceutically acceptable salt thereof; wherein the cancer is bone cancer, breast cancer, colorectal cancer, head and neck cancer, leukemia, lymphoma, myeloma, or ovarian cancer; 
       wherein:
 R 1  is —C(O)R 2 ; 
 R 2  is C 1-6  alkyl or C 6-14  aryl; 
 R 3  and R 5  are each independently hydrogen or deuterium; 
 R 4  is —C(R 4a ) 3 ; wherein each R 4a  is independently hydrogen or deuterium; and 
 R 6  is hydrogen or deuterium. 
 
     
     
       2. The method of  claim 1 , wherein R 2  is C 1-6  alkyl. 
     
     
       3. The method of  claim 1 , wherein R 2  is C 6-14  aryl. 
     
     
       4. The method of  claim 3 , wherein R 2  is phenyl. 
     
     
       5. The method of  claim 1 , wherein R 3  is hydrogen. 
     
     
       6. The method of  claim 1 , wherein R 5  is hydrogen. 
     
     
       7. The method of  claim 1 , wherein R 4a  is hydrogen. 
     
     
       8. The method of  claim 1 , wherein R 4a  is deuterium. 
     
     
       9. The method of  claim 1 , wherein R 4  is methyl. 
     
     
       10. The method of  claim 1 , wherein R 6  is hydrogen. 
     
     
       11. The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and tautomers and mixtures of two or more tautomers thereof; and pharmaceutically acceptable salts thereof. 
     
     
       12. The method of  claim 11 , wherein the compound is 6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yl benzoate, or a tautomer and a mixture of two or more tautomer thereof; or a pharmaceutically acceptable salt thereof. 
     
     
       13. The method of  claim 1 , wherein the bone cancer, breast cancer, colorectal cancer, head and neck cancer, leukemia, lymphoma, myeloma, and ovarian cancer are drug resistant. 
     
     
       14. The method of  claim 1 , wherein the cancer is leukemia. 
     
     
       15. The method of  claim 1 , wherein the cancer is lymphoma. 
     
     
       16. The method of  claim 1 , wherein the cancer is breast cancer. 
     
     
       17. The method of  claim 14 , wherein the leukemia is acute lymphoblastic leukemia or acute myelogenous leukemia.